The HSV-1 genome includes at least seventy-six open reading frames which encode at least seventy-three diverse polypeptides. The genes encoded by the viral genome have been classified into three major groups designated as .alpha.,.beta. and .gamma., whose expression is coordinately regulated and sequentially ordered in a cascade fashion. The .alpha. genes are expressed in the absence of prior viral protein synthesis. Expression of the .alpha. genes is induced by the interaction of an HSV structural protein designated as .alpha.-transinducing factor or virion protein No. 16 and several host proteins which interact with a response element located in the 5' untranscribed domains of all .alpha. genes. The products of the .alpha. genes trans-activate the expression of the .beta. genes by a mechanism as yet unknown, but the response elements for the induction of the .beta. genes appear to reside in their 5' untranscribed domains. Among the response elements commonly associated with .beta. gene promoters are TATAA boxes, SP1 binding sites, CCAAT boxes, and sites for binding of the .alpha.4 gene product. The expression of .gamma. genes also requires the expression of a genes. In addition, their expression is partially (the .gamma..sub.1 genes) or totally (the .gamma..sub.2 genes) dependent on viral DNA synthesis. In contrast to the .alpha. and .beta. genes, in .gamma. genes promoter response elements (including .alpha.4 protein binding sites) have been reported to be present in both 5' untranscribed and transcribed non-coding domains.
Various HSV promoters have been utilized to express non-HSV genes in the context of the HSV genome. Post et al., Mol. Cell. Biol., 2: 233-240 (1982) reports the expression of ovalbumin from a fusion of a chicken ovalbumin gene to the promoter of the .alpha.4 gene. Similarly, Hummel et al., Virology, 148: 337-343 (1986) describes the expression of an Epstein-Barr virus protein, the EBNA1 protein, from the .alpha.4 promoter in the HSV genome. Synthetic genes consisting of the coding sequences of a foreign gene fused to a specific HSV promoter and inserted into the HSV genome are expressed in the temporal class of the promoter as is reported, for example, in Shih et al., Proc. Natl. Acad. Sci. USA, 81: 5867-5870 (1984) where the hepatitis B virus S gene specifying the hepatitis B virus surface antigen was inserted into the HSV genome under the control of the HSV .alpha.4 gene promoter and separately under the control of the HSV thymidine kinase gene .beta. promoter.
While the HSV genome has been successfully utilized to express products of heterologous genes, inserting foreign genes under the control of native HSV promoters is problematic because of the sequential order of activation of HSV promoters. A foreign gene under the control of an HSV .alpha. promoter is transcribed early in the replicative process of the virus while a foreign gene under the control of an HSV .gamma. promoter is transcribed only in the later stages of replication. Heterologous polypeptides or proteins are therefore not continuously expressed throughout the infection cycle of the virus and the potential level of foreign protein synthesized is correspondingly reduced.
There thus continues to be a need in the art for HSV synthetic promoters specifically designed to express gene products throughout the infectious process of the virus and overproduce the gene product.